4, 8-epoxy-1, 3-dioxolane [4, 5-d]-1, 2-diaza compound as well as preparation method and application of 4, 8-epoxy-1, 3-dioxolane [4, 5-d]-1, 2-diaza compound

Abstract

The invention discloses a 4, 8-epoxy-1, 3-dioxolame [4, 5-d]-1, 2-diaza # imgabs 0 # compound as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to a 4, 8-epoxy-1, 3-dioxolame [4, 5-d]-1, 2-diaza # imgabs 1 # compound as well as a preparation method and application thereof in the aspect of preparing anti-tumor medicines. The structural general formula of the 4, 8-epoxy-1, 3-dioxolane [4, 5-d]-1, 2-diaza # imgabs2 # compound is shown in the specification, in the formula, R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy substituted benzyl, halogen substituted benzyl, phenyl, C1-C4 alkyl substituted phenyl, hydroxyl substituted alkyl and ethyoxyl carbonyl methyl; and R2 is selected from hydrogen, C1-C4 alkyl and benzyl. The 4, 8-epoxy-1, 3-dioxolame [4, 5-d]-1, 2-diaza # imgabs3 # compound provided by the invention has the advantages of novel structure, many modifiable sites, mild reaction conditions, cheap and easily available raw materials, few steps, simple operation, good stereoselectivity and simple synthesis method, and is suitable for industrial production. # imgabs4 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine Compounds and preparation methods thereof and applications in the preparation of anti-tumor drugs. Background Art

[0002] Azasugars are sugar derivatives in which the oxygen atoms on the sugar ring are replaced by nitrogen atoms, also known as iminosugars. In 1966, nojirimycin was first isolated from Streptomyces as an azasugar compound and its structure was determined (Inouye S, Tsuruoka T, Niida T. Structure of nojirimycin, sugar antibiotic with nitrogen in the ring. J Antibiotics, Ser A, 1966, 19 (6): 288.), and in 1967, Paulsen et al. synthesized the first artificial 1-deoxynojirimycin (Paulsen H, Sangster I, Heyns K. Monosaccharide mitstickstoffhaltigem Ring, XIII. Synthese und Reaktionen von Keto-piperidinosen. Chem Ber, 1967, 100 (3): 802.). Currently, many studies have shown that azasugar compounds have significant biological activities such as antiviral infection, anti-tumor and treatment of diabetes. For example, castanospermine, as a glucosidase inhibitor, can significantly inhibit the growth of tumors in nude mice, and its analogs can inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells (Pili R, Chang J, Partis RA, Mueller RA, Chrest FJ, Passaniti A. The alpha-glucosidase I inhibitor castanospermine alters endothelial cell glycosylation, prevents angiogenesis, and inhibits tumor growth. Cancer Res, 1995, 55 (13): 2920-2926.). Therefore, azasugar compounds and their derivatives have good development prospects in becoming therapeutic drugs for anti-tumor related diseases.

[0003] 1,3-Dioxolane[4,5-d]-1,2-diazepine This type of compound is a new type of azasugar compound, and is also a type of seven-membered heterocyclic compound with multiple physiological activities. It has high practicality and academic value. The raw materials in its synthesis process are cheap and easy to obtain, the yield is high, the impurity types and impurity content are relatively small, and it has great potential for development. This type of compound has a stable structure, is easy to store and is not volatile, so there will be no major storage problems. 1,3-Dioxolane [4,5-d]-1,2-diazapine Nitrogen-oxygen heterocyclic compounds are nitrogen-oxygen heterocyclic compounds that contain both nitrogen atoms and oxygen atoms. Due to their structural diversity, they show a wide range of biological activities and are widely used in medicinal chemistry. Therefore, the development of efficient and green synthesis methods for nitrogen-oxygen heterocyclic compounds has important application value.

[0004] Cancer is a disease caused by genes. When the genes that regulate cell growth mutate or are damaged, the cells lose control and continue to proliferate and divide to produce tumors. Due to its unlimited proliferation, transformation, and easy dispersion and metastasis, the clinical manifestations are high recurrence rates and mortality rates. According to the latest global cancer burden data in 2020 (provided by IARC), there were 19.29 million new cases of cancer worldwide in 2020. Therefore, cancer has become a medical problem that plagues the world.

[0005] With the development of society and science, cancer treatment methods have been continuously improved, from toxic attack treatment on cells to targeted treatment for cancer cells. The so-called molecular targeted therapy refers to the design and development of corresponding therapeutic drugs for the identified carcinogenic sites at the cellular molecular level. After entering the human body, the drug will specifically select and combine with the carcinogenic site, and then have a specific effect, causing the tumor cells to die without affecting the normal tissue cells around the tumor. The common characteristics of molecular targeted drugs are that they have little effect on normal tissue cells, mild toxicity, and slow onset of action. They inhibit the malignant biological behavior of tumor cells by specifically targeting one or several targets in tumor cells. Summary of the invention

[0006] The present invention provides a 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine as shown in formula I. The invention discloses a compound and a pharmaceutically acceptable salt thereof, and provides a method for preparing the compound and its application as a small molecule inhibitor in the treatment and / or prevention of various malignant tumor diseases such as non-small cell lung cancer, small cell lung cancer, colon cancer, breast cancer, melanoma, cervical cancer, liver cancer, prostate cancer, etc.

[0007]

[0008] Among them, R 1Selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy-substituted benzyl, halogen-substituted benzyl, phenyl, C1-C4 alkyl-substituted phenyl, hydroxy-substituted alkyl, ethoxycarbonylmethyl;

[0009] R 2 Selected from hydrogen, C1-C4 alkyl, benzyl.

[0010] Furthermore, R 1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 4-methoxybenzyl, 2-fluorobenzyl, phenyl, 4-methylphenyl, 2-hydroxyethyl, ethoxycarbonylmethyl;

[0011] R 2 Selected from hydrogen, methyl, benzyl.

[0012] Furthermore, the present invention preferably comprises the following compounds:

[0013] (3aR,4R,8R,8aR)-2,2,6-Trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0014] (3aR,4R,8R,8aR)-6-Isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0015] (3aR,4R,8R,8aR)-6-tert-Butyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0016] (3aR,4R,8R,8aR)-6-Cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0017] (3aR,4R,8R,8aR)-6-Cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0018] (3aR,4R,8R,8aR)-6-Cyclohexyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0019] (3aR,4R,8R,8aR)-6-Benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0020] (3aR,4R,8R,8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0021] (3aR,4R,8R,8aR)-6-(2-Fluorobenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0022] (3aR,4R,8R,8aR)-2,2-Dimethyl-6-phenylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0023] (3aR,4R,8R,8aR)-2,2-Dimethyl-6-(4-methylphenyl)hexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0024] 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -6-yl]ethanol;

[0025] 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -6-yl]ethyl acetate;

[0026] (3aR,4R,8R,8aR)-5-Benzyl-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0027] (3aR,4R,8R,8aR)-6-Benzyl-2,2,5-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0028] (3aS,4S,8S,8aS)-2,2,6-Trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0029] (3aS,4S,8S,8aS)-6-Ethyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0030] (3aS,4S,8S,8aS)-6-Isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0031] (3aS,4S,8S,8aS)-6-Cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine ;

[0032] (3aS,4S,8S,8aS)-6-Cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine .

[0033] The present invention also provides a method for preparing some compounds, comprising the following steps:

[0034]

[0035] Where R 1 , R 2 is the corresponding group at the corresponding position of the compound Q01-Q15 of the present invention. X represents a halogen, specifically bromine or chlorine. The starting material used in preparing the compound Q01-Q15 is D-ribose, and the starting material D-ribose can be replaced with L-ribose in preparing the compound Q16-Q20.

[0036] A pharmaceutical composition comprising 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine A compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0037] The present invention also provides 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine as shown in formula I The invention relates to the use of the compound or its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of anti-tumor drugs. The tumors include non-small cell lung cancer, colon cancer, breast cancer, melanoma and ovarian cancer.

[0038] Beneficial effects of the present invention:

[0039] The present invention provides 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine The structure of the compounds is novel, there are many sites that can be modified, and the reaction conditions are mild, the raw materials are cheap and easy to obtain, the steps are few, the operation is simple, and the stereoselectivity is good. The synthesis method of the compounds provided by the present invention is simple and suitable for industrial production. The compounds of the present invention show different degrees of tumor cell proliferation inhibition activity on A549, HCT116, MCF7, and A375 tumor cell lines, providing more new compounds for anti-tumor drugs. DETAILED DESCRIPTION

[0040] The present invention is further described in detail below with specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following embodiments, and all technologies realized based on the content of the present invention belong to the scope of the present invention.

[0041] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents and instruments used, they are all conventional reagent products that can be purchased commercially.

[0042] Example 1: (3aR, 4R, 8R, 8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q01)

[0043] Step A: Preparation of (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol

[0044] Weigh D-ribose (10.0 g, 66.7 mmol) and place it in a flask. Add 50 mL of acetone, slowly drop 0.5 mL of sulfuric acid in an ice bath, stir and react at room temperature for 1.5 h, then add triethylamine (TEA) to neutralize the reaction solution to neutrality. After most of the acetone is evaporated under reduced pressure, 11.87 g of a slightly yellow viscous liquid is obtained by column chromatography (PE:EA=2:1), with a yield of 93.7%.

[0045] Step B: Preparation of [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolan-4-yl]methyl p-toluenesulfonate

[0046] Weigh (3aR, 6R, 6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol (11.87 g, 62.4 mmol) into a flask, add pyridine to dissolve, slowly add p-toluenesulfonyl chloride (14.28 g, 74.9 mmol) in pyridine to the reaction system under ice bath, stir and react overnight at room temperature. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, evaporate most of the ethyl acetate under reduced pressure, and separate by column chromatography (PE:EA=5:1) to obtain 14.00 g of white solid, with a yield of 67.3%.

[0047] Step C: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation

[0048] [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl]methyl p-toluenesulfonate (0.35 g, 1.0 mmol), methylhydrazine sulfate (0.17 g, 1.2 mmol), acetonitrile (2 mL), triethylamine (0.55 mL, 4.0 mmol) were added to a flask and stirred at 35°C under nitrogen protection for overnight reaction. Most of the acetonitrile was evaporated under reduced pressure and separated by column chromatography (PE:EA=2:1) ​​to obtain 0.133 g of a slightly yellow waxy solid with a yield of 66.3%. (c0.7,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.88–4.86(m,1H),4.86–4.81(m,1H),4.80–4.73(m,1H),4.27(td,J=2.1,0.9Hz,1H), 2.75–2.71(m,1H),2.36(dd,J=11.3,2.0Hz,1H),2.34(s,3H),1.47(s,3H),1.35(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ111.42,91.50,82.78,82.73,78.76,59.98,46.24,26.02,24.54.HRMS(ESI)m / z:Calcd for C 9 H 17 N 2 O 3 ([M+H] +)201.12337; Found 201.12260.

[0049] Example 2: (3aR, 4R, 8R, 8aR)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q02)

[0050] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with isopropylhydrazine hydrochloride to obtain 0.116 g of a white solid with a yield of 50.6%. mp: 40.5-42.1. (c 0.5,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ6.86(d,J=3.3Hz,1H),4.93–4.91(m,1H),4.73–4.69(m,1H),4.56–4.52(m,1H),4.28–4.23(m,1H),3.52(hept ,J=6.4Hz,1H),1.49–1.45(m,4H),1.37–1.35(m,1H),1.29(s,3H),1.18(d,J=3.6Hz,3H),1.16(d,J=3.7Hz,3H). 13 C NMR(101MHz, CDCl3)δ111.67,92.90,84.19,82.26,79.84,47.54,44.02,24.59,20.78,20.71.HRMS(ESI)m / z:Calcd for C 11 H 21 N 2 O 3 ([M+H] + )229.15467; Found 229.15453.

[0051] Example 3: (3aR, 4R, 8R, 8aR)-6-tert-butyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q03)

[0052] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with tert-butylhydrazine hydrochloride to obtain 0.059 g of a light yellow solid with a yield of 24.2%. (c 0.5,CHCl 3 ). 1 H NMR (600 MHz, CDCl3 )δ4.90–4.83(m,1H),4.80–4.76(m,1H),4.70–4.67(m,1H),4.29–4.25(m,1H),2.76(dd, J=11.1,2.4Hz,1H),2.54(dd,J=11.1,1.8Hz,1H),1.46(s,3H),1.35(s,3H),0.98(s,9H). 13 CNMR (101MHz, CDCl 3 )δ111.07,92.03,83.02,82.61,79.13,55.20,50.37,26.11,24.97,24.59.HRMS(ESI)m / z:Calcd for C 12 H 32 N 2 O 3 ([M+H] + )243.17032; Found 243.16968.

[0053] Example 4: (3aR, 4R, 8R, 8aR)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q04)

[0054] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with cyclopropylhydrazine hydrochloride to obtain 0.140 g of white solid with a yield of 61.7%. mp: 98.7–99.6°C. (c 0.5,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.84–4.80(m,1H),4.80–4.78(m,1H),4.78–4.77(m,1H),4.34–4.20(m,1H),3.67(dd,J=12.0,2.3Hz,1H ),3.01(tt,J=6.8,3.6Hz,1H),2.46(dd,J=12.0,1.5Hz,1H),1.48(s,3H),1.35(s,3H),0.79–0.45(m,4H). 13 C NMR (101 MHz, CDCl 3 )δ111.69,95.30,83.26,82.05,79.82,44.42,31.22,26.05,24.60,6.32,6.22.HRMS(ESI)m / z:Calcd forC11 H 19 N 2 O 3 ([M+H] + )227.13902; Found 227.13887.

[0055] Example 5: (3aR, 4R, 8R, 8aR)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q05)

[0056] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with cyclopentylhydrazine hydrochloride to obtain 0.142 g of white solid with a yield of 55.7%. mp: 100.4-101.4℃. (c 0.25, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.93–4.88(m,1H),4.85–4.74(m,2H),4.25–4.19(m,1H),3.83(p,J=7.8Hz,1H),3.53( dd,J=12.3,2.3Hz,1H),2.49–2.22(m,1H),2.03–1.50(m,8H),1.48(s,3H),1.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ111.64,94.17,83.83,82.23,79.81,57.86,43.49,30.85,30.66,26.05,24.58,24.42,23.95.HRMS(ESI)m / z:Calcd for C 13 H 23 N 2 O 3 ([M+H] + )255.17032; Found255.17012.

[0057] Example 6: (3aR, 4R, 8R, 8aR)-6-cyclohexyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q06)

[0058] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with cyclohexylhydrazine hydrochloride to obtain 0.084 g of a light yellow solid with a yield of 31.3%. (c 0.5,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.95–4.90(m,1H),4.89–4.83(m,1H),4.80–4.73(m,1H),4.22–4.13(m,1H),3.3 9(dd,J=12.6,2.4Hz,1H),3.12(tt,J=10.4,3.7Hz,1H),2.30(dd,J=12.6,2.9Hz,0 H),2.01–1.94(m,1H),1.89(dt,J=12.2,3.2Hz,1H),1.79–1.68(m,2H),1.58(dt,J =12.6,3.1Hz,1H),1.45(s,3H),1.33(s,3H),1.28–1.21(m,2H),1.17–1.02(m,3H). 13 C NMR(101MHz, CDCl3)δ111.60,92.40,84.21,82.32,79.84,55.24,44.17,30.49,26.04,25.82,24.84,24.59.HRMS(ESI)m / z:Calcd for C 14 H 25 N 2 O 3 ([M+H] + )269.18597; Found 269.18518.

[0059] Example 7: (3aR, 4R, 8R, 8aR)-6-Benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q07)

[0060] Referring to the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with benzylhydrazine dihydrochloride to obtain 0.200 g of a white solid with a yield of 72.4%. mp: 107.5-109.1°C. (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ7.38–7.27(m,5H),4.94(d,J=5.7Hz,1H),4.80(d,J=5.7Hz,1H),4.71(s,1H),4.27(t,J=2.1Hz,1H),4.23(d,J=13.1 Hz,1H),4.05(d,J=13.1Hz,1H),3.61(dd,J=12.4,2.4Hz,1H),2.31(dt,J=12.4,1.5Hz,1H),1.50(s,3H),1.38(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ137.13,129.22,128.57,127.52,111.62,94.86,83.65,81.93,79.94,54.20,43.01,26.05,24.59.HRMS(ESI)m / z:Calcd for C 15 H 21 N 2 O 3 ([M+H] + )277.15467; Found 277.15390.

[0061] Example 8: (3aR, 4R, 8R, 8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q08)

[0062] Referring to the preparation method of Example 1, methylhydrazine sulfate in step C was replaced by 4-methoxybenzylhydrazine hydrochloride to obtain 0.232 g of white solid with a yield of 75.5%. mp: 58.9-61.6°C. (c 0.5,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.26(d,J=8.7Hz,3H),6.86(d,J=8.7Hz,2H),4.95–4.88(m,1H),4.83–4.78(m,1H),4.70–4.68(m,1H),4.29–4.24(m,1H),4.17(d,J= 12.8Hz,1H),3.98(d,J=12.9Hz,1H),3.79(s,3H),3.62(dd,J=12.4,2.4Hz,1H),2.34(dd,J=12.4,3.0Hz,1H),1.47(s,3H),1.36(s,3H). 13C NMR (101 MHz, CDCl 3 )δ159.10,130.46,129.67,114.02,111.69,94.69,83.66,81.97,79.94,55.28,53.52,43.05,26.02,24.55.HRMS(ESI)m / z:Calcd for C 16 H 23 N 2 O 4 ([M+H] + )307.16523; Found 307.16498.

[0063] Example 9: (3aR, 4R, 8R, 8aR)-6-(2-fluorobenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q09)

[0064] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced by 2-fluorobenzylhydrazine hydrochloride to obtain 0.115 g of a white solid with a yield of 38.9%. (c 0.25, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.42–7.34(m,1H),7.30–7.22(m,2H),7.15–7.07(m,1H),7.04(ddd,J=9. 7,8.2,1.2Hz,1H),4.97–4.90(m,1H),4.83–4.78(m,1H),4.75–4.68(m,1H), 4.36(d,J=13.3Hz,1H),4.30–4.27(m,1H),4.02(d,J=13.3Hz,1H),3.68(dd, J=12.7,2.4Hz,1H),2.39(dd,J=12.7,2.9Hz,1H),1.48(s,3H),1.36(s,3H). 13 C NMR (101 MHz, CDCl 3)δ161.63(d,J=246.0Hz),136.11,131.39(d,J=5.0Hz),129.20(d,J=8.0Hz),124.13(d,J=4.0Hz),115.47(d,J =22.0Hz),111.85,95.15,83.65,81.85,79.97,47.64(d,J=2.0Hz),43.17,26.01,24.59.HRMS(ESI)m / z:Calcd for C 15 H 20 FN 2 O 3 ([M+H] + )295.14525; Found295.14471.

[0065] Example 10: (3aR, 4R, 8R, 8aR)-2,2-dimethyl-6-phenylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q10)

[0066] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with phenylhydrazine hydrochloride to obtain 0.013 g of an orange-red solid with a yield of 5.0%. (c 0.25, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.19–7.14(m,2H),6.94–6.88(m,2H),6.79(tt,J=7.3,1.2Hz,1H),4.97–4.89(m,1H),4.80–4.72(m,1H),4.68–4. 62(m,1H),4.38–4.31(m,1H),3.40(dd,J=11.5,3.2Hz,0H),2.96(dd,J=11.5,2.1Hz,1H),1.41(s,3H),1.23(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ149.34,129.05,120.39,113.64,111.74,91.48,82.70,82.50,78.24,51.62,26.01,24.54.HRMS(ESI)m / z:Calcd for C 14 H 19 N 2 O 3 ([M+H] +)263.13902; Found 263.13828.

[0067] Example 11: (3aR, 4R, 8R, 8aR)-2,2-dimethyl-6-(4-methylphenyl)hexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q11)

[0068] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced by 4-methylphenylhydrazine hydrochloride to obtain 0.016 g of a yellow solid with a yield of 5.8%. (c 0.32,CHCl3). 1 H NMR (400 MHz, CDCl 3 )δ7.26(d,J=8.7Hz,3H),6.86(d,J=8.7Hz,2H),4.95–4.88(m,1H),4.83–4.78(m,1H),4.29–4.24(m,1H),4.17(d,J=12.8Hz,1 H),3.98(d,J=12.9Hz,1H),3.79(s,4H),3.62(dd,J=12.4,2.4Hz,1H),2.34(dd,J=12.4,3.0Hz,1H),1.47(s,3H),1.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ147.18,129.90,129.52,113.89,111.69,91.52,82.75,82.56,78.30,52.13,26.02,24.55,20.38.HRMS(ESI)m / z:Calcd for C 15 H 21 N 2 O 3 ([M+H] + )277.15467; Found277.15448.

[0069] Example 12: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 6-aminoethyl]ethanol (Q12)

[0070] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with 2-hydroxyethylhydrazine to obtain 0.088 g of a white solid with a yield of 38.2%. mp: 69.3-71.5°C. (c 0.1,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.88(d,J=5.7Hz,1H),4.75(d,J=5.7Hz,1H),4.62(s,1H),4.21(s,1H),3.75(dt,J=7.9,3.9Hz,2H),3.54(dd,J=13.6,2.6Hz ,1H),3.41(ddd,J=13.4,7.0,3.3Hz,1H),2.68(ddd,J=13.4,5.4,3.3Hz,1H),2.35(d,J=13.6Hz,1H),1.47(s,3H),1.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ112.28,96.28,83.41,81.39,79.53,61.78,51.94,42.81,25.97,24.65.HRMS(ESI)m / z:Calcd for C 10 H 19 N 2 O 4 ([M+H] + )231.13393; Found 231.13290.

[0071] Example 13: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of ethyl acetate (Q13)

[0072] Referring to the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with ethyl hydrazineacetate hydrochloride to obtain 0.118 g of a white solid with a yield of 43.5%. (c 0.25, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ5.02–4.95(m,1H),4.82–4.76(m,1H),4.69–4.62(m,1H),4.24–4.14(m,3H),4.04(d,J=16.9Hz,1H),3.53(d, J=2.4Hz,1H),3.51–3.46(m,1H),2.37(dd,J=12.7,2.9Hz,0H),1.46(s,3H),1.35(s,3H),1.27(t,J=7.1Hz,3H).13 C NMR (101 MHz, CDCl 3 )δ170.52,111.85,96.04,83.43,81.69,79.91,60.94,51.09,42.57,26.02,24.59,14.14.HRMS(ESI)m / z:Calcd for C 12 H 21 N 2 O 5 ([M+H] + )273.14450; Found 273.14429.

[0073] Example 14: (3aR, 4R, 8R, 8aR)-5-benzyl-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q14)

[0074] Referring to the preparation method of Example 1, (3aR, 4R, 8R, 8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine was obtained. (Q01).

[0075] Weigh (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine (1.00g, 5.0mmol) was placed in a flask, pyridine was added to dissolve, benzyl bromide (1.71g, 10.0mmol) was slowly added dropwise under stirring, and the reaction was stirred at room temperature for 3h. The reaction solution was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate for 2h, most of the ethyl acetate was evaporated under reduced pressure and separated by column chromatography (PE:EA=8:1), and 1.37g of white solid was obtained, with a yield of 94.6%. mp:125.8-127.9℃. (c 0.7, CHCl 3 ). 1 H NMR (600 MHz, CDCl 3)δ7.35(dd,J=7.8,1.4Hz,2H),7.32–7.27(m,2H),7.25–7.21(m,1H),4.8 6–4.80(m,1H),4.76–4.71(m,1H),4.56–4.45(m,1H),4.30–4.24(m,1H), 4.05(d,J=12.1Hz,1H),3.91(d,J=12.1Hz,1H),3.16(dd,J=11.7,2.1Hz, 1H),2.50(s,3H),2.29(dd,J=11.7,1.9Hz,1H),1.42(s,3H),1.32(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ137.44,129.49,128.40,127.16,111.17,93.19,83.62,82.92,79.45,50.24,42.77,42.10,26.04,24.49.HRMS(ESI)m / z:Calcd for C 16 H 23 N 2 O 3 ([M+H] + )291.17032; Found 291.16962.

[0076] Example 15: (3aR, 4R, 8R, 8aR)-6-Benzyl-2,2,5-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q15)

[0077] Referring to the preparation method of Example 7, (3aR, 4R, 8R, 8aR)-6-benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine was obtained. (Q07).

[0078] Compound Q07 and dimethyl sulfate were used, and the preparation method of Example 14 was referred to to obtain 0.165 g of a light yellow powdery solid with a yield of 67.3%. (c 0.3,CHCl 3 ). 1 H NMR (600 MHz, CDCl 3)δ7.37–7.32(m,2H),7.32–7.27(m,2H),7.25–7.21(m,1H),4.86–4.80 (m,1H),4.76–4.72(m,1H),4.53–4.48(m,1H),4.29–4.25(m,1H),4.05 (d,J=12.1Hz,1H),3.91(d,J=12.1Hz,1H),3.16(dd,J=11.7,2.1Hz,1H),2.50(s,3H),2.29(dd,J=11.7,3.0Hz,0H),1.42(s,3H),1.32(s,3H). 13 CNMR (101MHz, CDCl 3 )δ137.44,129.49,128.40,127.16,111.17,93.19,83.61,82.92,79.45,50.23,42.77,42.10,26.04,24.49.HRMS(ESI)m / z:Calcd for C 16 H 23 N 2 O 3 ([M+H] + )291.17032; Found291.16937.

[0079] Example 16: (3aS, 4S, 8S, 8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q16)

[0080] Step A: Preparation of (3aS,6S,6aS)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-ol

[0081] Weigh L-ribose (5.0 g, 33.3 mmol) and place it in a flask. Add acetone (25 mL). Slowly drop sulfuric acid (0.25 mL) in an ice bath. Remove the ice bath. Stir the reaction at room temperature for 1.5 h. Add triethylamine to neutralize the reaction solution until it is neutral. After most of the acetone is evaporated under reduced pressure, 5.37 g of a slightly yellow viscous liquid is obtained by column chromatography (PE:EA=2:1). The yield is 84.8%.

[0082] Step B: Preparation of [(3aS,4S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl]methyl p-toluenesulfonate

[0083] Weigh (3aS, 6S, 6aS)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran [3,4-d] [1,3] dioxolane-4-ol (5.37 g, 28.2 mmol) into a flask, add pyridine to dissolve, slowly add p-toluenesulfonyl chloride (5.38 g, 28.2 mmol) in pyridine under ice bath, stir and react overnight at room temperature. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate for 2 hours. After most of the ethyl acetate is evaporated under reduced pressure, column chromatography (PE: EA = 4: 1) is performed to obtain 6.22 g of white solid, with a yield of 64.0%.

[0084] Step C: (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation

[0085] [(3aS,4S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl]methyl p-toluenesulfonate (0.35 g, 1.0 mmol), methylhydrazine sulfate (0.17 g, 1.2 mmol), and triethylamine (0.55 mL, 4.0 mmol) were added to a flask and stirred at 35°C under nitrogen protection for overnight reaction. Most of the acetonitrile was evaporated under reduced pressure and then separated by column chromatography (PE:EA=2:1) ​​to obtain 0.110 g of a colorless waxy solid with a yield of 55.0%. (c 0.7, CHCl 3 ). 1 HNMR (600MHz, CDCl 3 )δ4.88–4.85(m,1H),4.85–4.82(m,1H),4.78–4.74(m,1H),4.29–4.24(m,1H),2.72(dd, J=11.3,2.2Hz,1H),2.36(dd,J=11.3,2.0Hz,1H),2.32(s,3H),1.46(s,3H),1.34(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ111.39,91.48,82.77,82.72,78.74,59.98,46.26,26.02,24.52.HRMS(ESI)m / z:Calcd for C 9 H 17 N 2 O([M+H] + ) 3 201.12337; Found 201.12262.

[0086] Example 17: (3aS, 4S, 8S, 8aS)-6-ethyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q17)

[0087] Referring to the preparation method of Example 16, methylhydrazine sulfate in step C was replaced with ethylhydrazine hydrochloride to obtain 0.111 g of a white solid with a yield of 52.0%. mp: 127.5-129.1°C. (c 0.52, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.89–4.86(m,1H),4.80–4.76(m,1H),4.70–4.67(m,1H),4.22–4.16(m,1H),3.51(dd,J=12.7,2.4Hz,1H),3.03(dq,J=12 .4,7.2Hz,1H),2.92(dq,J=12.2,7.3Hz,1H),2.33(dd,J=12.7,2.8Hz,1H),1.47(s,4H),1.36(s,3H),1.07(t,J=7.2Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ111.81,94.82,83.66,81.87,79.89,44.40,43.11,26.03,24.62,12.51.HRMS(ESI)m / z:Calcd for C 10 H 19 N 2 O 3 ([M+H] + )215.13902; Found 215.13892.

[0088] Example 18: (3aS, 4S, 8S, 8aS)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q18)

[0089] Referring to the preparation method of Example 16, the methylhydrazine sulfate in step C was replaced with isopropylhydrazine hydrochloride to obtain 0.122 g of a white solid with a yield of 53.3%. mp: 40.9-41.9°C. (c 0.25, CHCl 3 ).1 H NMR (400 MHz, CDCl 3 )δ4.91(s,1H),4.87(d,J=5.7Hz,1H),4.77(d,J=5.7Hz,1H),4.19(t,J=1.7Hz,1H),3.51(dq,J=12.8,6.5Hz,1H), 3.42(dd,J=12.6,2.4Hz,1H),2.32(dt,J=12.6,1.3Hz,1H),1.47(s,3H),1.35(s,3H),1.09(dd,J=6.2,4.7Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ111.66,92.90,84.20,82.26,79.83,47.53,44.02,26.04,24.59,20.79,20.72.HRMS(ESI)m / z:Calcd for C 11 H 21 N 2 O 3 ([M+H] + )229.15467; Found 229.15450.

[0090] Example 19: (3aS, 4S, 8S, 8aS)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q19)

[0091] Referring to the preparation method of Example 16, the methylhydrazine sulfate in step C was replaced with cyclopropylhydrazine hydrochloride to obtain 0.118 g of a white solid with a yield of 52.2%. mp: 99.0-99.4°C. (c 0.5,CHCl3). 1 H NMR (400 MHz, CDCl 3 )δ4.84–4.81(m,1H),4.81–4.78(m,1H),4.78–4.76(m,1H),4.33–4.22(m,1H),3.67(dd,J=12.0,2.3Hz,1H ),3.01(tt,J=6.6,3.6Hz,1H),2.46(dd,J=12.0,3.1Hz,1H),1.48(s,3H),1.35(s,3H),0.66–0.40(m,4H). 13 C NMR (101 MHz, CDCl 3)δ111.70,95.30,83.26,82.05,79.83,44.42,31.23,26.05,24.60,6.32,6.22.HRMS(ESI)m / z:Calcd forC 11 H 19 N 2 O 3 ([M+H] + )227.13902; Found 227.13896.

[0092] Example 20: (3aS, 4S, 8S, 8aS)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of (Q20)

[0093] Referring to the preparation method of Example 16, the methylhydrazine sulfate in step C was replaced with cyclopentylhydrazine hydrochloride to obtain 0.160 g of a white solid with a yield of 63.0%. (c 0.5,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ4.92–4.88(m,1H),4.84–4.75(m,2H),4.24–4.20(m,1H),3.90–3.76(m,1H),3.53(dd,J=1 2.3, 2.3Hz, 1H), 2.35 (dd, J=12.3, 2.9Hz, 0H), 1.93–1.57 (m, 8H), 1.48 (s, 4H), 1.36 (s, 3H). 13 CNMR (101MHz, CDCl 3 )δ111.64,94.17,83.82,82.23,79.81,57.86,43.49,30.84,30.65,26.05,24.58,24.41,23.95.HRMS(ESI)m / z:Calcd for C 13 H 23 N 2 O 3 ([M+H] + )255.17032; Found 255.17018.

[0094] 4,8-Epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Example of compound list

[0095]

[0096]

[0097]

[0098] Pharmacological Examples

[0099] Example 21: Inhibitory activity of the test compound on proliferation of non-small cell lung cancer A549, colon cancer HCT116, breast cancer MCF7, and melanoma A375 cells

[0100] (1) Experimental Materials

[0101] Tumor cell lines non-small cell lung cancer cells A549, colon cancer cells HCT116, breast cancer cells MCF7, and melanoma A375 cells were plated in 96-well plates at a density of 5000, 4000, 5000, and 4000 cells / well, respectively, with 100 μL per well, and used after 24 hours.

[0102] The target compound was dissolved in DMSO, diluted with culture medium to prepare six different concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM, and stored at -20°C until use. The final concentration of DMSO in the culture medium was less than 0.1%.

[0103] MTT: Dissolve in PBS to 2 mg / mL and store at -20°C.

[0104] (2) Experimental methods

[0105] A549, HCT116, MCF7, and A375 cells were selected to evaluate the anti-tumor proliferation activity of the test samples using the MTT method. A549, HCT116, MCF7, and A375 cell lines were cultured in DMEM medium containing 10% fetal bovine serum (FBS). When the cells proliferated to 80-90%, they were merged and then subcultured for no more than 20 generations, and then they were allowed to adapt to the environment for 24 hours before the next treatment. The cells were placed on a 96-well plate and then incubated in a 5% CO 2, and culture in an incubator at a constant temperature of 37°C until the cells are completely attached. After 24 hours, different concentrations of representative compounds of the invention are added. After another 24 hours of culture, MTT (2 mg / mL) is added and culture is continued for 4 hours. The culture matrix is ​​removed, the crystals are dissolved in DMSO, and the absorbance is measured at a wavelength of 570 nm using an enzyme reader (Thermo Multiskan GO, Thermo Fisher, USA). According to the formula: Cell growth inhibition rate = (1-drug group OD value / control group OD value) × 100%, the cell growth inhibition rate at the corresponding concentration is calculated, and a logarithmic curve is drawn with different concentrations of the test compound and the inhibition rate on the cells to calculate the corresponding IC 50 The representative compounds of the present invention were determined according to the above method.

[0106]

[0107]

[0108] Among the above target compounds, all compounds showed different degrees of tumor cell proliferation inhibition activity against A549, HCT116, MCF7, and A375 tumor cell lines, among which Q14 and Q16 had significant proliferation inhibition activity against A549 cell line, and their IC 50 were all lower than 20 μM. Q10 had significant inhibitory activity on the proliferation of HCT116 cells. Its IC 50 Nearly 10 μM, Q07 has a significant inhibitory activity on the proliferation of A375 cells, and its IC 50 All were below 20μM.

[0109] Formulation Examples

[0110] The following formulation examples are merely illustrative of the scope of the present invention, but are not intended to limit the scope of the present invention in any way. The active compounds described in the following examples are the target compounds prepared in the above examples.

[0111] Example 22: Tablet Formulation

[0112] Active compound 25-1000 mg, starch 45 mg, microcrystalline cellulose 35 mg, polyvinyl pyrrolidone (as a 10% aqueous solution) 4 mL, sodium carboxymethyl cellulose 4.5 mg, magnesium stearate 0.5 mg, talc 1 mg.

[0113] Example 23: Suspension Concentrate Formulation

[0114] Active compound 0.1-1000 mg, sodium carboxymethyl cellulose 50 mg, syrup 1.25 mg, sodium benzoate 0.1 mg, flavoring agent 25 mg, coloring agent 5 mg, add purified water to 5 mL.

[0115] Example 24: Aerosol Formulation

[0116] Active compound 0.25 mg, ethanol 25-75 mL, propellant 22 (chlorodifluoromethane) 70 mg.

[0117] Example 25: Suppository Formulation

[0118] Active compound 250mg, saturated fatty acid glycerides 2000mL.

[0119] Example 26: Injectable Formulation Formulation

[0120] Active compound 50 mg, isotonic saline solution 1000 mL.

[0121] Example 27: Ointment Formulation

[0122] 0.025 g of micronized active compound, 10 g of liquid paraffin, and add soft white wax to 100 g.

[0123] Example 28: Ointment Formulation

[0124] 0.025 g of active compound, 5 g of propylene glycol, 5 g of sorbitan sesquioleate, 10 g of liquid paraffin, and add soft white wax to 100 g.

[0125] Example 29: Oil-in-water cream formulation

[0126] Active compound 0.025g, hexadecanol 5g, glyceryl monostearate 5g, liquid paraffin 10g, cetyl alcohol polyoxyethylene ether 2g, citric acid 0.1g, sodium citrate 0.2g, propylene glycol 35g, add water to 100g.

[0127] Example 30: Oil-in-water cream formulation

[0128] 0.025 g of micronized active compound, 15 g of soft white wax, 5 g of liquid paraffin, 5 g of hexadecanol, 2 g of Sorbimacrogolstearate (Tween 65 of specific pharmaceutical excipient grade), 0.5 g of sorbitan monostearate, 0.2 g of sorbic acid, 0.1 g of citric acid, 0.2 g of sodium citrate, add water to 100 g.

[0129] Example 31: Water-in-oil cream formulation

[0130] 0.025g active compound, 35g soft white wax, 5g liquid paraffin, 5g dehydrated sorbitan sesquioleate, 0.2g sorbic acid, 0.1g citric acid, 0.2g sodium citrate, add water to 100g.

[0131] Example 32: Lotion Formulation

[0132] Active compound 0.25 g, isopropanol 0.5 mL, carboxyvinyl polymer 3 mg, NaOH 2 mg, add water to 1 g.

[0133] Example 33: Injectable suspension formulation

[0134] Active compound 10 mg, sodium carboxymethyl cellulose 7 mg, NaCl 7 mg, polyoxyethylene (20) sorbitan monooleate 0.5 mg, benzyl alcohol 8 mg, add sterile water to 1 mL.

[0135] Example 34: Aerosol Formulation for Oral and Nasal Inhalation

[0136] Active compound 0.1% w / w, Sorbitan trioleate 0.7% w / w, Trichlorofluoromethane 24.8% w / w, Dichlorotetrafluoroethane 24.8% w / w, Dichlorodifluoromethane 49.6% w / w.

[0137] Example 35: Nebulized solution formulation

[0138] Active compound 7 mg, propylene glycol 5 mg, add water to 10 g.

[0139] Example 36: Powder Formulation for Inhalation

[0140] Fill a clear gelatin capsule with the mixture of the following ingredients, 0.1 mg of micronized active compound, 20 mg of lactose, and inhale the powder with the aid of an inhalation device.

[0141] Example 37: Powder Formulation for Inhalation

[0142] The spheronized powder is filled into a multiple-dose powder inhaler, each dose containing 0.1 mg of the micronized active compound.

[0143] Example 38: Powder Formulation for Inhalation

[0144] The spheronized powder is filled into a multiple-dose powder inhaler, each dose containing 0.1 mg of micronized active compound and 1 mg of micronized lactose.

[0145] Example 39: Capsule Formulation

[0146] Active compound 1.0 mg, small sugar spheres 321 mg, Aquacoat ECD 30 6.6 mg, acetyl tributyl citrate 0.5 mg, Tween-80 0.1 mg, Eudragit L 100-55 17.5 mg, triethyl citrate 1.8 mg, talc 8.8 mg, defoaming agent MMS 0.1 mg.

[0147] Example 40: Capsule Seedling Formulation

[0148] Active compound 2.0 mg, small sugar spheres 305 mg, Aquocoat ECD 30 5.0 mg, acetyl tributyl citrate 0.4 mg, Tween-80 0.14 mg, Eudragit NE30D 12.6 mg, Eudragit S100 12.6 mg, talc 0.16 mg.

[0149] Example 41: Enema Formulation

[0150] Active compound 2 mg, sodium carboxymethyl cellulose 25 mg, disodium edetate 0.5 mg, methyl parahydroxybenzoate 0.8 mg, propyl parahydroxybenzoate 0.2 mg, sodium chloride 7 mg, citric acid 1.8 mg, Tween-80 0.01 mg, add purified water to 1 mL.

[0151] Example 42: Formulation containing liposomes

[0152] A. Preparation of Instillation Formulation

[0153] Dipalmitoylphosphatidylcholine (45 mg), dimyristoylphosphatidylcholine (7 mg), dipalmitoylphosphatidylglycerol (1 mg) and active compound (5 mg) were placed in a glass tube, and all components were dissolved in chloroform and heated with N 2 Most of the solvent was evaporated and then the pressure was reduced, thereby forming a lipid film on the surface of the glass tube. An aqueous solution (0.9% NaCl) was added to the lipid to form liposomes at a temperature higher than the phase transition temperature of the lipid. The resulting suspension contained liposomes ranging in size from extremely small vesicles to 2 μm.

[0154] B. Preparation of Formulations for Inhalation

[0155] Liposomes were prepared according to Example A, wherein the aqueous solution contained 10% lactose, and the ratio of lactose to lipid was 7:3. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronized to obtain particles with a mass mean aerodynamic diameter (MMAD) of about 2 μm.

[0156] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any person skilled in the art may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims

1. A 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine as shown in formula I A compound or a pharmaceutically acceptable salt thereof, characterized in that: The structure of formula I is: wherein R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy-substituted benzyl, halogen-substituted benzyl, phenyl, C1-C4 alkyl-substituted phenyl, hydroxy-substituted alkyl, ethoxycarbonylmethyl; R2 is selected from hydrogen, C1-C4 alkyl, benzyl.

2. The 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine according to claim 1 A compound or a pharmaceutically acceptable salt thereof, characterized in that: In the formula I, R1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 4-methoxybenzyl, 2-fluorobenzyl, phenyl, 4-methylphenyl, 2-hydroxyethyl, ethoxycarbonylmethyl; R2 is selected from hydrogen, methyl, benzyl.

3. 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine according to claim 2 A compound or a pharmaceutically acceptable salt thereof, characterized in that: Any one of the following compounds: Q01: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q02: (3aR,4R,8R,8aR)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q03: (3aR,4R,8R,8aR)-6-tert-butyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q04: (3aR,4R,8R,8aR)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q05: (3aR,4R,8R,8aR)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q06: (3aR,4R,8R,8aR)-6-cyclohexyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q07: (3aR,4R,8R,8aR)-6-Benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q08: (3aR,4R,8R,8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q09: (3aR,4R,8R,8aR)-6-(2-fluorobenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q10: (3aR,4R,8R,8aR)-2,2-Dimethyl-6-phenylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q11: (3aR,4R,8R,8aR)-2,2-dimethyl-6-(4-methylphenyl)hexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q12: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -6-yl]ethanol; Q13: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -6-yl]ethyl acetate; Q14: (3aR,4R,8R,8aR)-5-Benzyl-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q15: (3aR,4R,8R,8aR)-6-Benzyl-2,2,5-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q16: (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q17: (3aS,4S,8S,8aS)-6-ethyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q18: (3aS,4S,8S,8aS)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q19: (3aS,4S,8S,8aS)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Q20: (3aS,4S,8S,8aS)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine 4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine according to any one of claims 1 to 3 as an active ingredient. A compound of any one of the compounds or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier or diluent.

5. The 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine according to any one of claims 1 to 3 Use of compounds or pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs.

6. Use of the pharmaceutical composition according to claim 4 in the preparation of anti-tumor drugs.

7. The use according to any one of claims 5-6, characterized in that: The tumors include lung cancer, colon cancer, melanoma, breast cancer and ovarian cancer.

8. The 4,8-epoxy-1,3-dioxolane [4,5-d]-1,2-diazepine according to claim 3 A method for preparing a compound or a pharmaceutically acceptable salt thereof, characterized in that: The preparation route includes: Wherein R1 and R2 are corresponding groups at corresponding positions of compounds Q01-Q15 described in claim 3; X represents bromine or chlorine; when preparing compounds Q16-Q20, the starting material D-ribose is replaced by L-ribose.

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